The treatment of metastatic renal cell carcinoma (RCC) has been revolutionized by advances in immunotherapeutic and targeted agents. Therapeutic approaches to RCC in these categories have recently evolved to include immune checkpoint inhibitors, novel vascular endothelial growth factor receptor–targeting tyrosine kinase inhibitors, and combinations of those agents. Multiple regimens within each category have been approved for use in the first-line treatment of clear cell and non–clear cell RCC. However, few of these regimens have been directly compared, leading to a new clinical challenge for physicians: how to select a first-line treatment regimen for an individual patient from among multiple approved options. In the modern era of RCC management, the initial treatment selection therefore becomes highly personalized and depends on numerous patient-specific factors, including histopathologic and clinical features of the disease, comorbid conditions, and psychosocial and economic factors. This review details current first-line treatment options for the management of metastatic RCC and proposes a framework whereby treatment selection can be optimized for individual patients.